Articular cartilage is a thin, smooth, low friction, gliding surface composed of hyaline cartilage with resiliency to compressive forces. While only a few millimeters thick, it has excellent wear characteristics. Its mechanical and structural capacity depends on the integrity of its extracellular matrix, in which chondrocytes are sparsely distributed throughout structural macromolecules including collagen, proteoglycans, and noncollagenous proteins. Although chondrocyte cells produce the extracellular matrix, they compose less than 5% of the wet weight of cartilage.
The composition and highly complicated interaction of these components make regeneration and replacement techniques challenging. For example, the lack of a direct blood supply and few cells distributed widely among a dense extracellular matrix leads to a limited healing ability of damaged articular cartilage. This has led to a wide variety of treatment approaches for defects, for example, in the knee, with varying levels of success.
Procedures such as drilling, abrasion, microfracture, and debridement provide symptomatic pain relief and improved function. Collectively, these procedures may be referred to as subchondral bone marrow stimulation techniques where the bone underlying the cartilage, which has a rich blood supply, is caused to bleed. The goal of such procedures is to mobilize mesenchymal stem cells from the blood to differentiate into chondrocyte-like cells that synthesize repair tissue. Once the vascularized cancellous bone is disrupted, a fibrin clot forms and pluripotent cells migrate into the area. These cells eventually differentiate into chondrocyte-like cells that secrete type I, type II and other collagen types, as well as cartilage specific proteoglycans, after receiving appropriate mechanical and biological cues. The cells produce a fibroblastic repair tissue that on appearance and initial biopsy can have a hyaline-like quality, but over time, is demonstrated histologically as being predominantly fibrocartilaginous tissue. Fibrocartilage is a relatively disorganized lattice of collagen fibers, as opposed to the natural hyaline cartilage, and thus partially fills the defect with structurally weak tissue that also exhibits limited durability.
Other procedural options such as periosteal grafting, osteochondral autografts and allografts, and autogenous chondrocyte cell implantation have been used to repair cartilage defects for the purpose of reducing pain and restoring function. The success of these procedures generally diminishes over time, possibly due to formation of fibrocartilage, inadequate development of repair tissue, poor cell differentiation, and/or poor bonding to the surrounding articular cartilage borders. Intact full thickness grafts, such as osteochondral autografts and allografts, also may suffer from mismatched sizes, immunologic rejection, and poor adhesion of cartilage to bony surfaces. For autogenous chondrocyte cell implantation, two surgeries are required: chondrocytes are first obtained from an uninvolved area of cartilage and cultured for 14 to 21 days, then the cultured cells are injected into the defect exposed via an open incision and covered with a periosteal flap excised from the proximal medial tibia.
Various methods of promoting tissue growth and repair, and in particular cartilage repair, have been suggested and include the use of tissue particles derived from grinding non-demineralized, articular cartilage into pieces of about 60 μm to about 500 μm (Malinin U.S. Patent Application No. 20050196460); mincing tissue into particles using two parallel blades, resulting in particles of about 0.1 to about 3 mm3 in size and containing at least one viable cell (Binette et al. U.S. Patent Application No. 20040078090); pulverizing soft tissue into morsels of about 1 to about 100 μm that may then be combined with viable elements (cells) and/or bioactive molecules (Awad et al. U.S. Patent Application No. 20050288796); and, milling allograft cartilage, which is then lyophilized to create particles in the size of about 0.01 mm to about 1 mm that can be formulated into a paste (Gomes et al. U.S. Patent Application No. 20040219182). Various methods of tissue preparation have also been disclosed including a method of generating dermal tissue pieces of about 50 μm to about 1500 μm using a roller with multiple blades (Mishra et al. U.S. Patent Application No. 20040175690).
Cell and/or tissue viability for implants needs to be improved. For example, homogenizers used to generate tissue particles have resulted in about 5% of the cells remaining viable following homogenization. Enzymatic digestion, which is often used to generate cells for autogenous chondrocyte cell transplantation, results in poor cell viability following initial isolation.
Improved compositions and methods for repairing tissue defects and in particular, articular cartilage defects are desired.